{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:57:15Z","timestamp":1790787435333,"version":"4.1.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T00:00:00Z","timestamp":1724716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Gut microbiome (GM) was observed to be associated with the incidence of Hirschsprung disease (HD). However, the effect and mechanism of GM in HD is still unclear. To investigate the relationship between GM and HD and the effect of metabolites as mediators, a bidirectional two-step Mendelian randomization (MR) study was conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study selected instrument variables (IVs) from summary-level genome-wide association studies (GWAS). The MiBioGen consortium provided the GWAS data for GM, while the GWAS data for metabolites and HD were obtained from the GWAS Catalog consortium. Two-sample MR analyses were performed to estimate bidirectional correlations between IVs associated with GM and HD. Then, genetic variants related to 1,400 metabolite traits were selected for further mediation analyses using the Product method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This study found that seven genus bacteria had a significant causal relationship with the incidence of HD but not vice versa. 27 metabolite traits were significantly correlated with HD. After combining the significant results, three significant GM-metabolites-HD lines have been identified. In the <jats:italic>Peptococcus<\/jats:italic>-Stearoyl sphingomyelin (d18:1\/18:0)-HD line, the Stearoyl sphingomyelin (d18:1\/18:0) levels showed a mediation proportion of 14.5%, while in the <jats:italic>Peptococcus<\/jats:italic>-lysine-HD line, the lysine levels had a mediation proportion of 12.9%. Additionally, in the <jats:italic>Roseburia<\/jats:italic>-X-21733-HD line, the X-21733 levels played a mediation proportion of 23.5%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our MR study indicates a protective effect of <jats:italic>Peptococcus<\/jats:italic> on HD risk that is partially mediated through serum levels of stearoyl sphingomyelin (d18:1\/18:0) and lysine, and a risk effect of <jats:italic>Roseburia<\/jats:italic> on HD that is partially mediated by X-21733 levels. These findings could serve as novel biomarkers and therapeutic targets for HD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2024.1371933","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T04:44:42Z","timestamp":1724733882000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The mediating role of metabolites between gut microbiome and Hirschsprung disease: a bidirectional two-step Mendelian randomization study"],"prefix":"10.3389","volume":"12","author":[{"given":"Zhe","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiwu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1177\/1093526619892351","article-title":"Diagnosis of hirschsprung disease","volume":"23","author":"Ambartsumyan","year":"2020","journal-title":"Pediatr Dev Pathol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/nrgastro.2017.149","article-title":"Hirschsprung disease\u2014integrating basic science and clinical medicine to improve outcomes","volume":"15","author":"Heuckeroth","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/s00383-016-3862-9","article-title":"Established and emerging concepts in hirschsprung\u2019s-associated enterocolitis","volume":"32","author":"Gosain","year":"2016","journal-title":"Pediatr Surg Int"},{"key":"B4","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/35079107","article-title":"Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn\u2019s disease","volume":"411","author":"Hugot","year":"2001","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.jpedsurg.2009.06.009","article-title":"Murine model of Hirschsprung-associated enterocolitis. 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